As cancer treatments continue to become more effective with increases in patient survival, we are recognizing clinical consequences of therapy that negatively impact the course of therapy and the quality of life of patients and survivors. Of major clinical significance is chemotherapy-induced peripheral neuropathy (CIPN), which can be severe enough to necessitate reducing or stopping treatment and thus can compromise therapy. Furthermore, CIPN can continue long after therapy is stopped and is irreversible in a significant number of patients. Compounding this problem is a lack of effective treatments available to prevent or reverse CIPN. The lack of effective prevention or treatment for CIPN is a direct consequence of not understanding the mechanisms that cause the neurotoxicity. As such, examining the provocative question of ?What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?? will be addressed in our studies using animal models and an array of endpoints measuring changes in sensory neuronal function which parallel clinical symptoms of CIPN. Most CIPN develops over time with few if any acute symptoms after initial therapy, but increases in severity with continued therapy. The delay in onset of neuropathy suggests that there is an aggregate effect of drugs over time that results in a long-term alteration in neuronal function. Consequently, it is important to examine the mechanisms by which cumulative exposure to chemotherapeutics might result in neurotoxicity. Previously, we demonstrated that reducing the activity of the DNA base excision repair (BER) pathway by reducing expression of the apurinic/apyrimidinic endonuclease/redox factor (APE1/Ref-1 or APE1) exacerbated neurotoxicity produced by anticancer treatment, whereas augmenting the repair activity of APE1 attenuated the neurotoxicity. These data support the notion that DNA damage is a critical mechanism by which the function of sensory neurons is altered by chemotherapeutics. Indeed, it is likely that in post-mitotic cells (e.g. neurons) DNA damage could result in abnormal protein production that is maintained unless the DNA damage is repaired, reversing the aberrant transcriptional effects of the neurotoxins. Therefore, we hypothesize that APE1 is a critical protein for protecting neurons from cancer therapies and that augmenting APE1 DNA repair activity will prevent and reverse chemotherapy-induced alterations in sensory neuronal function. Furthermore, fully understanding the DNA damage and the mechanisms by which the BER pathway reverses this damage will lead to the identification of novel targets for CIPN prevention or therapy. To address these hypotheses, we propose three aims which will determine whether augmenting APE1 repair activity in vivo prevents or reverses DNA damage in sensory neurons and the subsequent alterations in sensory neuronal function caused by anticancer drug administration as well as determining the mechanisms mediating APE1-induced neuroprotection of isolated sensory neurons.